1. Grading evidence and recommendations The GRADE initiative Holger Schünemann, MD, PhD Associate Professor Italian National Cancer Institute Regina Elena, Rome

2. Professional good intentions and plausible theories are insufficient for selecting policies and practices for protecting, promoting and restoring health. Iain Chalmers

3. How can we judge the extent of our confidence that adherence to a recommendation will do more good than harm?

4. GRADE G rades of R ecommendation A ssessment, D evelopment and E valuation

5. What do you know about GRADE? o Have prepared a guideline o Read the BMJ paper o Have prepared a systematic review and a summary of findings table o Have attended a GRADE meeting, workshop or talk

6. About GRADE* o Began as informal working group in 2000 o Researchers/guideline developers with interest in methodology o Aim: to develop a common system for grading the quality of evidence and the strength of recommendations that is sensible and to explore the range of interventions and contexts for which it might be useful* o 13 meetings (~10 – 35 attendants) o Evaluation of existing systems and reliability* o Workshops at Cochrane Colloquia, WHO, GIN and various conferences since 2000 *Grade Working Group. CMAJ 2003, BMJ 2004, BMC 2004, BMC 2005

7. GRADE Working Group David Atkins, chief medical officer a Dana Best, assistant professor b Martin Eccles, professor d Francoise Cluzeau, lecturer x Yngve Falck-Ytter, associate director e Signe Flottorp, researcher f Gordon H Guyatt, professor g Robin T Harbour, quality and information director h Margaret C Haugh, methodologist i David Henry, professor j Suzanne Hill, senior lecturer j Roman Jaeschke, clinical professor k Regina Kunx, Associate Professor Gillian Leng, guidelines programme director l Alessandro Liberati, professor m Nicola Magrini, director n James Mason, professor d Philippa Middleton, honorary research fellow o Jacek Mrukowicz, executive director p Dianne O’Connell, senior epidemiologist q Andrew D Oxman, director f Bob Phillips, associate fellow r Holger J Schünemann, associate professor g,s Tessa Tan-Torres Edejer, medical officer t Jane Thomas, Lecturer, UK Helena Varonen, associate editor u Gunn E Vist, researcher f John W Williams Jr, professor v Stephanie Zaza, project director w a) Agency for Healthcare Research and Quality, USA b) Children's National Medical Center, USA c) Centers for Disease Control and Prevention, USA d) University of Newcastle upon Tyne, UK e) German Cochrane Centre, Germany f) Norwegian Centre for Health Services, Norway g) McMaster University, Canada h) Scottish Intercollegiate Guidelines Network, UK i) Fédération Nationale des Centres de Lutte Contre le Cancer, France j) University of Newcastle, Australia k) McMaster University, Canada l) National Institute for Clinical Excellence, UK m) Università di Modena e Reggio Emilia, Italy n) Centro per la Valutazione della Efficacia della Assistenza Sanitaria, Italy o) Australasian Cochrane Centre, Australia p) Polish Institute for Evidence Based Medicine, Poland q) The Cancer Council, Australia r) Centre for Evidence-based Medicine, UK s) National Cancer Institute, Italy t) World Health Organisation, Switzerland u) Finnish Medical Society Duodecim, Finland v) Duke University Medical Center, USA w) Centers for Disease Control and Prevention, USA x) University of London, UK

8. What do users want from guidelines? users looking for different things just tell me what to do (recommendation) what to do, and on strong or weak grounds recommendation and grade recommend, grade, evidence summary, values systematic review, value statement evidence from individual studies

9. When to make a recommendation? never patient values differ just lay out benefits and risks when evidence strong enough when very weak, too uncertain clinicians need guidance intense study demands decision

10. Why bother about grading? People draw conclusions about the – –quality of evidence – –strength of recommendations Systematic and explicit approaches can help – –protect against errors – –resolve disagreements – –facilitate critical appraisal – –communicate information However, there is wide variation in currently used approaches

11. Who is confused? Evidence Recommendation II-2B II-2B C+ 1 C+ 1 StrongStrongly recommended StrongStrongly recommendedOrganization  USPSTF  ACCP  GCPS

12. Still not confused? EvidenceRecommendation BClass I BClass I C+ 1 C+ 1 IVC IVCOrganization  AHA  ACCP  SIGN Recommendation for use of oral anticoagulation in patients with atrial fibrillation and rheumatic mitral valve disease

13. Grading System current profusion: can there be consensus? trade-off benefits and risks do it (or don’t do it) probably do it (or probably don’t do it) quality of underlying evidence high quality (well done RCT) intermediate (quasi-RCT) low (well done observational) very low (anything else)

14. Moving down poor RCT design, implementation randomization, concealment, follow-up inconsistency indirect patients, interventions, outcomes A vs B, but have A to C, B to C reporting bias

15. Moving up magnitude of effect dose-response biases favor control

16. Guidelines development process Prioritise Problems, establish panel  Systematic Review  Evidence Profile  Relative importance of outcomes  Overall quality of evidence  Benefit – downside evaluation  Strength of recommendation  Implementation and evaluation of guidelines

17. Guidelines development process Prioritise Problems, establish panel  Systematic Review  Evidence Profile  Relative importance of outcomes  Overall quality of evidence  Benefit – downside evaluation  Strength of recommendation  Implementation and evaluation of guidelines

18. Example ACCP First ACCP guidelines in 1986 (J. Hirsh; J. Dalen)First ACCP guidelines in 1986 (J. Hirsh; J. Dalen) Initially aimed at consensusInitially aimed at consensus Methodologists involved since beginningMethodologists involved since beginning Now formally convening every 2 to 3 yearsNow formally convening every 2 to 3 years Seventh conference held in 2003; > 200.000 copies published in ChestSeventh conference held in 2003; > 200.000 copies published in Chest 87 panel members, 22 chapters87 panel members, 22 chapters Across subspecialtiesAcross subspecialties 565 recommendations, 230 new565 recommendations, 230 new Evidence Based RecommendationsEvidence Based Recommendations Next conference in 2006Next conference in 2006

19.  Evidence –recommendation:transparent link  Explicit inclusion criteria  Comprehensive search  Standardized considerationof study quality  Conduct/use meta-analysis  Evaluate overall quality ofevidence  Grade recommendations  Acknowledge values andpreferences What makes guidelines evidence based (in 2005)? Schünemann et al. Chest 2004

20. Judgements about the overall quality of evidence Most systems not explicit Most systems not explicit Options: Options: –strongest outcome –primary outcome –benefits –weighted –separate grades for benefits and harms –no overall grade –weakest outcome Based on lowest of all the critical outcomes Based on lowest of all the critical outcomes Beyond the scope of a systematic review Beyond the scope of a systematic review

21. Quality of evidence “The extent to which one can be confident that an estimate of effect or association is correct.” It depends on the: –study design (e.g. RCT, cohort study) –study quality/limitations (protection against bias; e.g. concealment of allocation, blinding, follow-up) –consistency of results –directness of the evidence including the populations (those of interest versus similar; for example, older, sicker or more co-morbidity) populations (those of interest versus similar; for example, older, sicker or more co-morbidity) interventions (those of interest versus similar; for example, drugs within the same class) interventions (those of interest versus similar; for example, drugs within the same class) outcomes (important versus surrogate outcomes) outcomes (important versus surrogate outcomes) comparison (A - C versus A - B & C - B) comparison (A - C versus A - B & C - B)

22. Quality of evidence The quality of the evidence (i.e. our confidence) may also be REDUCED when there is:  Sparse or imprecise data  Reporting bias The quality of the evidence (i.e. our confidence) may be INCREASED when there is:  A strong association  A dose response relationship  All plausible confounders would have reduced the observed effect  All plausible biases would have increased the observed lack of effect

23. Quality assessment criteria

24. Categories of quality High: Further research is very unlikely to change our confidence in the estimate of effect. High: Further research is very unlikely to change our confidence in the estimate of effect. Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low: Any estimate of effect is very uncertain. Very low: Any estimate of effect is very uncertain.

25. Strength of recommendation “The extent to which one can be confident that adherence to a recommendation will do more good than harm.” quality of the evidence quality of the evidence translation of the evidence into practice in a specific setting translation of the evidence into practice in a specific setting uncertainty about baseline risk uncertainty about baseline risk trade-offs (the relative value attached to the expected benefits, harms and costs) trade-offs (the relative value attached to the expected benefits, harms and costs)

26. Clarity of the trade-offs between benefits and the harms the estimated size of the effect for each main outcome the estimated size of the effect for each main outcome the precision of these estimates the precision of these estimates important factors that could be expected to modify the size of the expected effects in specific settings; e.g. proximity to a hospital important factors that could be expected to modify the size of the expected effects in specific settings; e.g. proximity to a hospital the relative value attached to the expected benefits and harms the relative value attached to the expected benefits and harms the variation in values between people the variation in values between people

27. ← Option 1 (pink card) Option 2 → (green card)

28. You are hiking. Which of the following animals would you prefer to encounter?

29. ← Option 1 (pink card) Option 2 → (green card)

30. You are buying an ice cream. Which flavor do you prefer?

31. ← Option 1 (pink card) Option 2 → (green card) Chocolate Strawberry

32. You are buying a new car. Which one would you buy?

33. ← Option 1 (pink card) Option 2 → (green card) Yellow fox Red Ferrari

34. Judgements about the balance between benefits and harms Before considering cost and making a recommendation Before considering cost and making a recommendation

35. Judgements about recommendations

36. “We recommend”…”should” …“Do it” “We recommend”…”should” …“Do it” “We suggest”…”may” … “Probably do it” “We suggest”…”may” … “Probably do it” “We recommend not”… “may not” …“Probably don’t do it” “We recommend not”… “may not” …“Probably don’t do it” “We suggest not”…”should not”… “Don’t do it” “We suggest not”…”should not”… “Don’t do it” No recommendation This could include considerations of costs; i.e. “Is the net gain (benefits-downsides) worth the costs?”

37. Should healthy asymptomatic postmenopausal women have been given oestrogen + progestin for prevention in 1992? Quality of evidence across studies for Quality of evidence across studies for –CHD –Hip fracture –Colorectal cancer –Breast cancer –Stroke –Thrombosis –Gall bladder disease Quality of evidence across critical outcomes Quality of evidence across critical outcomes Balance between benefits and harms Balance between benefits and harms Recommendations Recommendations Will GRADE lead to change?

38. Oestrogen + progestin for prevention after WHI and HERS

40. Further GRADE developments Diagnostic tests Diagnostic tests Costs Costs (Equity) (Equity) Empirical evaluations Empirical evaluations Free software application Free software application

41. GRADE Profiler (GRADEpro)

42. GRADE profiler (GRADEpro)

48. GRADE Profile Excel, HTML, MS Word format Linked to REVMAN (direct import from REVMAN)

52. Comparison of GRADE and other systems Explicit definitions Explicit definitions Explicit, sequential judgements Explicit, sequential judgements Components of quality Components of quality Overall quality Overall quality Relative importance of outcomes Relative importance of outcomes Balance between health benefits and harms Balance between health benefits and harms Balance between incremental health benefits and costs Balance between incremental health benefits and costs Consideration of equity Consideration of equity Evidence profiles Evidence profiles International collaboration International collaboration Software Software Consistent judgements? Consistent judgements? Communication? Communication?

53. Who is interested in GRADE WHO WHO American Endocrine Society American Endocrine Society American College of Chest Physicians (ACCP) American College of Chest Physicians (ACCP) Italian National Cancer Institute, Rome Italian National Cancer Institute, Rome Clinical Evidence Clinical Evidence Norwegian Centre for Health Services Norwegian Centre for Health Services UpToDate UpToDate Close relationship with Cochrane Collaboration Close relationship with Cochrane Collaboration American Society of Clinical Oncology (ASCO) American Society of Clinical Oncology (ASCO) American Thoracic Society (ATS) American Thoracic Society (ATS) Urologists worldwide Urologists worldwide

54. Empirical evaluations Critical appraisal of other systemsCritical appraisal of other systems Pilot test + sensibilityPilot test + sensibility “Case law” + practical experience“Case law” + practical experience Guidance for judgementsGuidance for judgements Single studiesSingle studies Sparse data or imprecise dataSparse data or imprecise data AgreementAgreement Validity?Validity? Comparisons with other systemsComparisons with other systems Alternative presentationsAlternative presentations